Drug-drug and drug-disease interactions contribute to the variability in response observed when a patient population is treated with standard doses of drugs. Pharmacokinetic techniques provide a means to identify and quantitate such interactions, and to assess their potential clinical relevance. This research project will investigate certain drug-drug and drug-disease interactions which involve drugs which are excreted by the kidneys or agents which are highly bound to plasma proteins. Individual protocols are designed with two major purposes. The first purpose is to provide data which will promote greater understanding of the mechanisms (physiologic, pharmacokinetic or biochemical) responsible for drug-drug or drug-disease interactions. The second purpose is to provide specific clinically useful information about the relevance of certain drug interactions or disease interactions about which little or no information is available. Two areas on which we propose to focus are the effects of heparin on the plasma protein binding of various compounds and the pharmacologic effects and disposition of disopyramide, a potent antiarrhythmic agent. Although the literature is replete with interactions involving the effect of heparin on the plasma protein binding of various compounds, we feel that much of the data suggests that in vitro effects on drug binding may have been occurring which were interpreted as in vivo effects. Studies are needed to clarify this observation in order to further an understanding of the mechanism(s) by which heparin affects drug binding to plasma proteins. With regard to disopyramide, we propose to study this drug in depth. It is one of only a few oral antiarrhythmic agents available and therefore in depth studies are clinically relevant. Moreover, the compound is a racemic mixture of two optical isomers, d- and l-disopyramide. Knowledge of the disposition and pharmacologic properties of the individual isomers and how they affect one another will contribute to a better understanding and, ultimately, to improved therapy with disopyramide. In addition, this type of information will add to our basic concepts of both pharmacologic properties and interactions of optical isomers.